The role of CEMIP in cancers and its transcriptional and post-transcriptional regulation.

CEMIP is a protein known for inducing cell migration and binding to hyaluronic acid. Functioning as a hyaluronidase, CEMIP primarily facilitates the breakdown of the extracellular matrix component, hyaluronic acid, thereby regulating various signaling pathways. Recent evidence has highlighted the significant role of CEMIP in different cancers, associating it with diverse pathological states. While identified as a biomarker for several diseases, CEMIP's mechanism in cancer seems distinct. Accumulating data suggests that CEMIP expression is triggered by chemical modifications to itself and other influencing factors. Transcriptionally, chemical alterations to the CEMIP promoter and involvement of transcription factors such as AP-1, HIF, and NF-κB regulate CEMIP levels. Similarly, specific miRNAs have been found to post-transcriptionally regulate CEMIP. This review provides a comprehensive summary of CEMIP's role in various cancers and explores how both transcriptional and post-transcriptional mechanisms control its expression.

USP4 promotes the proliferation and glucose metabolism of gastric cancer cells by upregulating PKM2.

BACKGROUND: The pyruvate kinase enzyme PKM2 catalyzes the final step in glycolysis and converts phosphoenolpyruvate (PEP) to pyruvate. PKM2 is often overexpressed in cancer and plays a role in the Warburg effect. The expression of PKM2 can be regulated at different levels. While it has been proven that PKM2 can be regulated by ubiquitination, little is known about its de-ubiquitination regulation. METHODS: Immunoprecipitation was applied to identify the PKM2 interaction protein and to determine the interaction region between PKM2 and USP4. Immunofluorescence was performed to determine the cellular localization of USP4 and PKM2. The regulation of PKM2 by USP4 was examined by western blot and ubiquitination assay. MTT assays, glucose uptake, and lactate production were performed to analyze the biological effects of USP4 in gastric cancer cells. RESULTS: USP4 interacts with PKM2 and catalyzes the de-ubiquitination of PKM2. Overexpression of USP4 promotes cell proliferation, glucose uptake, and lactate production in gastric cancer cells. Knockdown of USP4 reduces PKM2 levels and results in a reduction in cell proliferation and the glycolysis rate. CONCLUSIONS: USP4 plays a tumor-promoting role in gastric cancer cells by regulating PKM2.

Ubiquitin specific peptidases and prostate cancer.

Protein ubiquitination is an important post-translational modification mechanism, which regulates protein stability and activity. The ubiquitination of proteins can be reversed by deubiquitinating enzymes (DUBs). Ubiquitin-specific proteases (USPs), the largest DUB subfamily, can regulate cellular functions by removing ubiquitin(s) from the target proteins. Prostate cancer (PCa) is the second leading type of cancer and the most common cause of cancer-related deaths in men worldwide. Numerous studies have demonstrated that the development of PCa is highly correlated with USPs. The expression of USPs is either high or low in PCa cells, thereby regulating the downstream signaling pathways and causing the development or suppression of PCa. This review summarized the functional roles of USPs in the development PCa and explored their potential applications as therapeutic targets for PCa.

Hsa-miR-22-3p inhibits liver cancer cell EMT and cell migration/ invasion by indirectly regulating SPRY2.

The general mechanism for microRNAs to play biological function is through their inhibition on the expression of their target genes. In cancer, microRNAs may accelerate cell senescence, block angiogenesis, decrease energy supplies, repress tumor cell cycle and promote apoptosis to function as the tumor repressors. On the other hand, microRNAs can modulate tumor suppressor molecules to activate oncogene relevant signaling pathway to initiate tumorigenesis and promote tumor progression. By targeting different genes, miR-22 can function as either a tumor suppressor or a tumor promoter in different types of cancer. In liver cancer, miR-22 mainly functions as a tumor suppressor via its regulation on different genes. In this study, we demonstrated that miR-22 indirectly regulates SPRY2 by inhibiting CBL, an E3 ligase for SPRY2 that has been confirmed. As one of the modulators of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling pathway, SPRY2 plays important roles in many developmental and physiological processes, and its deregulation has been reported in different types of cancer and shown to affect cancer development, progression, and metastasis. By inhibiting the expression of CBL, which stabilizes SPRY2, miR-22 indirectly upregulates SPRY2, thereby suppressing the epithelial-mesenchymal transition (EMT), cell migration, and invasion and decreasing the expression of liver cancer stem cell (CSC) marker genes. The inhibitory effects of miR-22 on EMT, cell migration, and invasion can be blocked by the knockdown of SPRY2 expression in miR-22 overexpressing cells. Additionally, we demonstrated that miR-22 expression inhibits the ERK signaling pathway and that this effect is due to its upregulation of SPRY2. Overall, our study revealed a novel miR-22-3p/CBL/SPRY2/ERK axis that plays an important role in EMT, cell migration, and invasion of liver cancer cells.

Roles of ubiquitination in the crosstalk between tumors and the tumor microenvironment (Review).

The interaction between a tumor and the tumor microenvironment (TME) plays a key role in tumorigenesis and tumor progression. Ubiquitination, a crucial post­translational modification for regulating protein degradation and turnover, plays a role in regulating the crosstalk between a tumor and the TME. Thus, identifying the roles of ubiquitination in the process may assist researchers to investigate the mechanisms underlying tumorigenesis and tumor progression. In the present review article, new insights into the substrates for ubiquitination that are involved in the regulation of hypoxic environments, angiogenesis, chronic inflammation­mediated tumor formation, and the function of cancer­associated fibroblasts and infiltrating immune cells (tumor­associated macrophages, T­cells, myeloid­derived suppressor cells, dendritic cells, and natural killer cells) are summarized. In addition, the potential targets of the ubiquitination proteasome system within the TME for cancer therapy and their therapeutic effects are reviewed and discussed.

Electrochemical Sensor for the Detection of 1-Hydroxypyrene Based on Composites of PAMAM-Regulated Chromium-Centered Metal-Organic Framework Nanoparticles and Graphene Oxide.

A nanocomposite was formed by combining graphene oxide (GO) with chromium-centered metal-organic framework (Cr-MOF) nanoparticles regulated by the dendrimer polyamidoamine (PAMAM). PAMAM can successfully regulate the synthesis of Cr-MOF; in doing so, the size of Cr-MOF is reduced, its original morphology is maintained, and it has good crystallinity. A simple ultrasonication method was used to make the Cr-MOF/GO hybrid nanocomposite. Various characterization methods confirmed the successful synthesis of PAMAM/Cr-MOF/GO nanocomposites. The PAMAM/Cr-MOF/ERGO modified electrode could be used with cyclic voltammetry (CV) and differential pulse voltammetry (DPV) to study the electrochemical behaviors of 1-hydroxypyrene (1-OHPyr). The results indicated that the constructed PAMAM/Cr-MOF/ERGO electrochemical sensor had a significantly enhanced electrocatalytic effect on the electrochemical reduction of 1-OHPyr compared with the sensors with no PAMAM and the ERGO sensor, which could be ascribed to the synergetic effect from the high porosity of Cr-MOF and the high conductivity of ERGO, as well as the further electron transport action of the nanocomposite. Under the optimal conditions, the reduction peak current and concentration of 1-OHPyr showed a good linear relationship in the range of 0.1-1.0 and 1.0-6.0 µM, and the detection limit of 1-OHPyr was calculated to be 0.075 µM. Moreover, the PAMAM/Cr-MOF/ERGO electrochemical sensor constructed in this paper can be expected to provide some instructions for the construction of electrochemical sensing platforms and wider potential applications.

Cu-MOF/hemin: a bionic enzyme with excellent dispersity for the determination of hydrogen peroxide released from living cells.

The stability, repeatability and sensitivity of an electrochemical biosensor material are closely connected with the dispersibility of metal organic frameworks (MOFs) in aqueous media. Herein, a nanocomposite based on Cu-MOF/hemin, which is not only highly water-soluble but also simple and efficient in synthesis, was used for the construction of a non-enzymatic sensor to detect hydrogen peroxide (H2O2). The Cu-MOF/hemin was characterized via scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS)-mapping, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and thermal gravimetric analysis (TGA), which indicate that hemin and the Cu-MOF were successfully combined. As a H2O2 electrochemical biomimetic enzyme, the Cu-MOF/hemin exhibited excellent electrocatalytic performance, which was confirmed by the electrochemical experiments and chromogenic reactions, and the possible mechanism of the reactions has been deduced. The electrochemical sensor based on the biomimetic enzyme exhibited an extended linear detection range from 0.01-5.0 mM (R = 0.998), low detection limit of 4.14 µM, and high selectivity and stability under the optimized conditions. More importantly, the practical application ability of the sensor was verified by the test of H2O2 in human serum samples and it could be used for the real-time detection of H2O2 released from living cells with satisfactory results. Therefore, this novel nanocomposite has certain potential in preparing electrochemical sensing platforms for nonenzymatic biosensing and provides a new method for clinical diagnosis and real-time monitoring.

miR-219-5p targets TBXT and inhibits breast cancer cell EMT and cell migration and invasion.

miR-219-5p has been reported to act as either a tumor suppressor or a tumor promoter in different cancers by targeting different genes. In the present study, we demonstrated that miR-219-5p negatively regulated the expression of TBXT, a known epithelial-mesenchymal transition (EMT) inducer, by directly binding to TBXT 3'-untranslated region. As a result of its inhibition on TBXT expression, miR-219-5p suppressed EMT and cell migration and invasion in breast cancer cells. The re-introduction of TBXT in miR-219-5p overexpressing cells decreased the inhibitory effects of miR-219 on EMT and cell migration and invasion. Moreover, miR-219-5p decreased breast cancer stem cell (CSC) marker genes expression and reduced the mammosphere forming capability of cells. Overall, our study highlighted that TBXT is a novel target of miR-219-5p. By suppressing TBXT, miR-219-5p plays an important role in EMT and cell migration and invasion of breast cancer cells.

Ubiquitination of Nonhistone Proteins in Cancer Development and Treatment.

Ubiquitination, a crucial post-translation modification, regulates the localization and stability of the substrate proteins including nonhistone proteins. The ubiquitin-proteasome system (UPS) on nonhistone proteins plays a critical role in many cellular processes such as DNA repair, transcription, signal transduction, and apoptosis. Its dysregulation induces various diseases including cancer, and the identification of this process may provide potential therapeutic targets for cancer treatment. In this review, we summarize the regulatory roles of key UPS members on major nonhistone substrates in cancer-related processes, such as cell cycle, cell proliferation, apoptosis, DNA damage repair, inflammation, and T cell dysfunction in cancer. In addition, we also highlight novel therapeutic interventions targeting the UPS members (E1s, E2s, E3s, proteasomes, and deubiquitinating enzymes). Furthermore, we discuss the application of proteolysis-targeting chimeras (PROTACs) technology as a novel anticancer therapeutic strategy in modulating protein target levels with the aid of UPS.